DESCRIPTION: It has been shown in recent years that structural and functional defects of mitochondrial proton-translocating NADH-ubiquinone oxidoreductase (complex I) are involved in many human diseases. These diseases include Leber's hereditary optic neuropathy, Parkinson's disease, dystonia, severe lactic acidosis, various forms of encephalomyopathies, and possibly Huntington's disease. Dysfunction of complex I presents three problems: (1) Impairment of the ability of the respiratory chain to oxidize NADH back to NAD4 which is required, among other things, for operation of the citric acid cycle and fatty acid oxidation enzymes. (2) Impairment of the ability of this enzyme to pump protons, resulting in a decrease in the rate of ATP synthesis. (3) Production of superoxide radicals, causing mitochondrial DNA (mtDNA) mutation, lipid peroxidation, and protein denaturation. Mammalian complex I is composed of at least 41 unlike subunits and has the most intricate structure among the membrane-bound enzyme complexes. Of these subunits, seven are encoded by mtDNA and synthesized within the mitochondrion, and other are cytoribosomal products. At present, mutations and deletions of the subunits encoded by MtDNA are not correctable, and mutations of plural subunits encoded by nuclear ONA (nDNA) are difficult to repair. The overall goal of this grant application is to find a remedy for the diseases that result from dysfunction of complex I.